Lead inhibits osteoblastic bone formation and osteoclastic bone resorption. Their data suggest that the effect is more pronounced in osteoblasts than in osteoclasts, thus leading to a negative bone balance. However, the mechanism by which Pb has its effects on these cell types is not fully understood. They have at their disposal the appropriate cell and animal models and molecular reagents to uncover how Pb interferes with normal bone cell processes. n the case of bone formation, they focus on a newly discovered osteoblast regulatory protein, TRIP. TRIP modulates TGF signaling and thus could be a key factor in osteoblast differentiation and activity. TRIP expression is markedly blunted by exposure to Pb. n the case of bone resorption they will focus their investigations on RANK ligand, OPG and the transcription factor, NFkappaB. Their preliminary data indicate that Pb depresses RANK ligand synthesis and up regulates OPG synthesis. Both of these effects contribute to a decrease in osteoclastic bone resorption. Moreover, as NFkappaB is central to osteoclast function it is an important target to investigate. Again, their preliminary data show that Pb depresses NFkappaB signaling. In parallel with the in vitro studies, they will examine their hypothesis in an in vivo animal model. Utilizing sophisticated in situ hybridization techniques and immunohistochemical methods developed specifically for bone they can determine if Pb exposure in a whole animal regulates bone resorption and bone formation by affecting TRIP, RAND ligand, OPG and NFkappaB expression.